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Interleukin (IL)-6 is a pro-inflammatory cytokine that also affects metabolic function because IL-6 depleted (IL-6−/−) mice develop late-onset obesity. IL-6 appears to act in the central nervous system, presumably in the hypothalamus, to increase energy expenditure that appears to involve stimulation of the sympathetic nervous system. In the present study, we explored possible central mechanisms for the effects exerted by IL-6 on body fat. Therefore, we measured the effects of IL-6 depletion in IL-6−/− mice on expression of key hypothalamic peptide genes involved in energy balance by the real time polymerase chain reaction. Additionally, co-localisation between such peptides and IL-6 receptor α was investigated by immunohistochemistry. IL-6 deficiency decreased the expression of several peptides found in the paraventricular nucleus (PVN), which is a nucleus that has been attributed an adipostatic function. For example, corticotrophin-releasing hormone (CRH), which is reported to stimulate the sympathetic nervous system, was decreased by 40% in older IL-6−/− mice. Oxytocin, which is reported to prevent obesity, was also decreased in older IL-6−/− animals, as was arginine vasopressin (AVP). The IL-6 receptor α was abundantly expressed in the PVN, but also in the supraoptic nucleus, and was shown to be co-expressed to a high extent with CRH, AVP, oxytocin and thyrotrophin-releasing hormone. These data indicate that depletion of endogenous IL-6, a body fat suppressing cytokine, is associated with the decreased expression of CRH and oxytocin (i.e. energy balance regulating peptides) as well as AVP in the PVN. Because IL-6 receptor α is co-expressed with CRH, oxytocin and AVP, IL-6 could stimulate the expression of these peptides directly. [ABSTRACT FROM AUTHOR]

Abstract Exposing rats to repeated restraint stress induces well-characterized adaptations in the expression of either corticotropin-releasing factor (CRF) or arginine-vasopressin (AVP) mRNA in the parvocellular neurons of the hypothalamic paraventricular nucleus (PVN). The effects of regulating corticosterone levels on this adaptation was studied in male rats. In intact rats, acute restraint stress increased the expression of CRF mRNA whilst AVP mRNA expression was no different to control. Repeated exposure resulted in habituation of CRF expression, whereas AVP mRNA increased above that seen in either non stressed or acutely stressed animals. In adrenalectomised rats with replacement pellets of corticosterone that replicated blood levels approximating to the daily trough (mean levels 37–65 ng/mL), basal CRF expression levels were raised, but the response to acute stress was still observed. However, the habituation seen in normal animals that had been repeatedly stressed was prevented, so that CRF mRNA levels continued to be raised after repeated stress. By contrast, the AVP response to both acute and repeated stress was unaltered in these low-dose corticosterone-treated rats compared with controls. Higher dose pellets, which resulted in blood levels around those of the daily maximum (mean 118–141 ng/mL) had the opposite effects. There was no change compared to intact rats in the expression of CRF mRNA following either acute or repeated stress, but the expected increase in AVP following repeated restraint was prevented. These experiments show that corticosterone has important modulating effects on the adaptive pattern of both CRF and AVP mRNA expression in the parvocellular PVN. The ‘set-point’ of corticosterone differs; for CRF, experiencing higher levels is necessary for subsequent adaptation to repeated restraint to occur, whereas for AVP a return to lower levels is necessary to allow this peptide to respond to repeated stress. [ABSTRACT FROM AUTHOR]